کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1364709 981544 2006 11 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Synthesis and radiosynthesis of [18F]FPhEP, a novel α4β2-selective, epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors
کلمات کلیدی
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Synthesis and radiosynthesis of [18F]FPhEP, a novel α4β2-selective, epibatidine-based antagonist for PET imaging of nicotinic acetylcholine receptors
چکیده انگلیسی

FPhEP (1, (+/−)-2-exo-(2′-fluoro-3′-phenyl-pyridin-5′-yl)-7-azabicyclo[2.2.1]heptane) belongs to a recently described novel series of 3′-phenyl analogues of epibatidine, which not only possess subnanomolar affinity and high selectivity for brain α4β2 neuronal nicotinic acetylcholine receptors (nAChRs), but also were reported as functional antagonists of low toxicity (up to 15 mg/kg in mice). FPhEP (1, Ki of 0.24 nM against [3H]epibatidine) as reference as well as the corresponding N-Boc-protected chloro- and bromo derivatives (3a,b) as precursors for labelling with fluorine-18 were synthesized in eight and nine steps, respectively, from commercially available N-Boc-pyrrole (overall yields = 17% for 1, 9% for 3a and 8% for 3b). FPhEP (1) was labelled with fluorine-18 using the following two-step radiochemical process: (1) no-carrier-added nucleophilic heteroaromatic ortho-radiofluorination from the corresponding N-Boc-protected chloro- or bromo derivatives (3a,b—1 mg) and the activated K[18F]F–Kryptofix®222 complex in DMSO using microwave activation at 250 W for 1.5 min, followed by (2) quantitative TFA-induced removal of the N-Boc-protective group. Radiochemically pure (>99%) [18F]FPhEP ([18F]-1, 2.22–3.33 GBq, 66–137 GBq/μmol) was obtained after semi-preparative HPLC (Symmetry® C18, eluent aq 0.05 M NaH2PO4/CH3CN, 80:20 (v:v)) in 75–80 min starting from a 18.5 GBq aliquot of a cyclotron-produced [18F]fluoride production batch (10–20% nondecay-corrected overall yield). In vitro binding studies on rat whole-brain membranes demonstrated a subnanomolar affinity (KD 660 pM) of [18F]FPhEP ([18F]-1) for nAChRs. In vitro autoradiographic studies also showed a good contrast between nAChR-rich and -poor regions with a low non-specific binding. Comparison of in vivo Positron Emission Tomography (PET) kinetics of [18F]FPhEP ([18F]-1) and [18F]F-A-85380 in baboons demonstrated faster brain kinetics of the former compound (with a peak uptake at 20 min post injection only). Taken together, the preliminary data obtained confirm that [18F]FPhEP ([18F]-1) has potential for in vivo imaging nAChRs in the brain with PET.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 14, Issue 11, 1 June 2006, Pages 3848–3858
نویسندگان
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